Selective Endothelin-Receptor Antagonist to Reduce Blood Pressure - Selective Endothelin-Receptor Antagonist to Reduce Blood Pressure


The goal of the trial was to evaluate treatment with the selective endothelin-receptor antagonist darusentan in patients with treatment-resistant hypertension.


Darusentan would be more effective in controlling hypertension.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patients Screened: 718
Patients Enrolled: 379
Mean Follow Up: 14 weeks
Mean Patient Age: 62 years
Female: 50

Patient Populations:

  • Systolic blood pressure >140 mm Hg (or >130 mm Hg with diabetes or chronic kidney disease) on three antihypertensive medications, including a full-dose diuretic
  • Body mass index between 20 and 43 kg/m2
  • Estimated glomerular filtration rate >30 ml/min/1.73 m2


  • Systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg
  • Heart failure
  • Poorly controlled diabetes
  • Anemia
  • Liver disease
  • Coronary (including arrhythmias) or cerebrovascular events in the last 6 months

Primary Endpoints:

  • Change from baseline to week 14 in systolic and diastolic blood pressure

Secondary Endpoints:

  • Change from baseline to final measurement in mean 24-hour systolic and diastolic blood pressure
  • Percentage of patients who reached goal systolic blood pressure
  • Change from baseline in estimated glomerular filtration rate
  • Safety and tolerability of darusentan

Drug/Procedures Used:

Patients with treatment-resistant hypertension were randomized to darusentan 50 mg (n = 81), darusentan 100 mg (n = 81), darusentan 300 mg (n = 85), or placebo (n = 132).

Concomitant Medications:

At baseline, 58% of patients were on four or more antihypertensive agents. Diuretics were used in 99%, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers in 97%, calcium-channel blockers in 74%, beta-blockers in 66%, and other antihypertensive agents in 21%.

Principal Findings:

Overall, 379 patients were randomized. The mean age was 62 years, 50% were women, mean body mass index was 32 kg/m2, 40% had type 2 diabetes, mean blood pressure was 151/86 mm Hg, and mean 24-hour systolic/diastolic pressure was 135/78 mm Hg.

Over 14 weeks of follow-up, the mean reduction in systolic and diastolic blood pressure was 17/10 mm Hg with darusentan 50 mg, 18/10 with darusentan 100 mg, 18/11 with darusentan 300 mg, and 9/5 mm Hg with placebo (p < 0.0001 for all effects). The results were similar when stratified by gender, age, and presence of diabetes/chronic kidney disease. There was no evidence for a dose response relation for darusentan over the dosages tested. Edema or fluid retention occurred in 27% of the darusentan group versus 14% of the placebo group.


Among patients with treatment-resistant hypertension, the addition of darusentan is beneficial. This agent resulted in a significant reduction in systolic and diastolic blood pressures compared with placebo. The three doses of darusentan that were tested (50, 100, and 300 mg) produced similar reductions in blood pressure. Edema or fluid retention was more common with darusentan, which is not uncommon with vasodilatory drugs.


Weber MA, Black H, Bakris G, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet 2009;Sep 14:[Epub ahead of print].

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Statins, Hypertension

Keywords: Follow-Up Studies, Endothelins, Diuretics, Diabetes Mellitus, Type 2, Pyrimidines, Blood Pressure, Edema, Systole, Body Mass Index, Glomerular Filtration Rate, Hypertension, Phenylpropionates, Renal Insufficiency, Chronic

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